1. Field of the Invention
This invention is concerned with diagnostic methods which assist in classification of tumors by phenotype and with therapeutic intervention tailored to particular tumor phenotypes. In particular this invention concerns mutant forms of type II receptors (RII) for transforming growth factor beta (TGF-.beta.) which inactivate growth suppression by TGF-.beta., methods for detecting inactivation of TGF-.beta. RII receptor and therapeutic methods for restoring tumor suppression by restoring RII function.
2. Review of Related Art
TGF-.beta. inhibits growth of multiple epithelial cell types, and loss of this negative regulation is thought to contribute to tumor development (Roberts, et al., 1990, In Peptide Growth Factors and Their Receptors. Handbook of Experimental Pharmacology, A. Roberts and M. Sporn, Eds., (Springer-Verlag, Heidelberg) pp. 419-472; Massague, J., 1990, Annu. Rev. Cell Biol, 6:597; Moses, et al., 1990, Cell, 63:247; Filmus, et al., 1993, Curr. Opin. Oncol., 5:123; Markowitz, S., et al., 1994, J. Clin. Invest., 93:1005; Wu, S., et al., 1992, J. Cell. Biol., 116:187; Wu, S., et al., 1993, Cell Growth Differ., 4:115; Park, J., et al., 1994, Proc. Natl. Acad. Sci. U.S.A., 91:8772; Manning, et al., 1991, Oncogene, 6:1471; Hoosein, N., et al., 1989, Exp. Cell Res., 181:442; Geiser, et al., 1992, J. Biol. Chem., 267:2588). Previous studies have demonstrated that TGF-.beta. suppresses growth of certain cancer cell lines, that antisense inhibition of TGF-.beta. enhances the tumorigenicity of weakly tumorigenic cancer cell lines, and that certain tumor cells can become unresponsive to TGF-.beta. (Markowitz, S., et al., 1994, J. Clin. Invest., 93:1005; Wu, S., et al., 1992, J. Cell. Biol., 116:187; Wu, S., et al., 1993, Cell Growth Differ., 4:115; Park, J., et al., 1994, Proc. Natl. Acad. Sci. U.S.A., 91:8772; Manning, et al., 1991, Oncogene, 6:1471; Hoosein, N., et al., 1989, Exp. Cell Res., 181:442; Geiser, et al., 1992, J. Biol. Chem., 267:2588).
The TGF-.beta. growth inhibitory signal is transduced through two receptors, type I (RI) and type II (RII) which function as a heteromeric complex (Lin, et al., 1992, Cell, 68:775; Moustakas, A., et al., 1993, J. Biol. Chem., 268:22215; Wrana, J., et al., 1992, Cell, 71:1003).